Pulmonary hypertension (PH), defined as the increase of mean pulmonary artery pressure (PAP) above normal values, encompasses a series of diseases characterized by the increase of pulmonary vascular resistances (PVRs) and progressive deterioration of the right ventricle (RV) function (McLaughlin 2009). In this regard, most studies refer to PH for mean PAP values above 25 mmHg, considering that a typical mean PAP in humans is about 12 to 15 mmHg.
There are many causes of PH which have been classified into 5 groups: pulmonary arterial hypertension (PAH); PH due to left heart disease; PH due to lung disease; chronic thromboembolic PH; and PH of an unknown or multifactorial origin. Unlike other groups, PH due to left heart disease is of a post-capillary origin, characterized by the increase of pulmonary capillary pressure.
The incidence of PH in the population is high and it is associated with high morbidity and mortality. Approximately two thirds of patients with left ventricular dysfunction (isolated diastolic or systolic) develop PH.
Currently, there is a lack of treatments for PH. Advances in the development of new pharmacological therapies have focused on idiopathic PH, the least frequent subgroup (prevalence of 6 cases per million people). In this subgroup the first line treatment is calcium-antagonists, which are only effective over the long term in 1% of the cases. Other treatments using vasodilators, such as prostaglandins (Barst 1996), 5-phosphodiesterase inhibitors (Galié 2005) or endothelin receptor antagonists (Channick 2001), provide benefits in a higher percentage of patients, although their clinical and hemodynamic effect is small (mean PAH reduction of 2-10%). In addition, these treatments have not proven consistent efficiency in pulmonary hypertension due to a left cardiac pathology (the most frequent), nor in the remaining pulmonary hypertension groups generally.
There has been little research on β3 adrenergic receptors in the field of cardiovascular diseases. Stimulation of these receptors is associated with the production of nitric oxide and the relaxation of vascular tone. In a study with rat lung samples, stimulation of β3 adrenergic receptors produced dose-dependent relaxation (Dumas 1998). In a functional study of rings of pulmonary artery extracted from dogs, an increase of relaxation with selective stimulation of β1, β2 and β3 adrenergic receptors was observed (Tagaya 1999). However, in another study in which pulmonary arteries were extracted from control mice and from mice with hypoxia-induced PH, increase of relaxation with selective stimulation of β3 receptors was not observed (Leblais, 2008).